Method of treatment of aggression

ABSTRACT

The invention comprises a method of treatment of aggression and similar behavioral syndromes, such as impulsivity and irritability, by a pharmaceutical agent exhibiting combined D2 and D5 antagonistic activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/782,334, filed Oct. 12, 2017, which is a Continuation of U.S. patentapplication Ser. No. 13/951,642, filed Jul. 26, 2013, which is aContinuation of U.S. application Ser. No. 12/654,455, filed Dec. 18,2009, which claims priority from U.S. Provisional Application No.61/193,735, filed Dec. 19, 2008, the entire contents of which areincorporated herein by reference.

BACKGROUND

Aggression and similar syndromes, including impulsivity andirritability, represent a broad category of behaviors that complicatethe management of several disease states, such as attention deficithyperactivity disorder (ADHD), bipolar disorder, autism, and posttraumatic stress disorder. In some cases, 25-50% of patients optimallytreated for the underlying disorder continue to manifest these syndromes(J Am Acad Child Adolesc Psychiatry. 2007 March; 46(3):309-22.).

Dopaminergic therapies are among the most prescribed for thesebehavioral syndromes, and include such molecules as haloperidol andother antipsychotics. The dopamine receptors for these molecules aregrouped into 2 families: the D1, which includes the D1 and D5 receptor,and the D2, which includes the D2, D3 and D4 receptors. The two familiesdiffer by the manner in which the receptor protein is incorporated intothe cell membrane, and by the pharmacology of the molecules that have anaffinity for each type. Each receptor type is a distinct entity with itsunique gene, anatomy in the brain and affinity for different molecules.Some dopamine receptor subtypes, such as the D2 receptor, have furthermodifications in the protein structure, giving rise to furthersubclassification, e.g., D2_(short) and D2_(long).

There is increasing evidence that D5 receptor activity would bebeneficial in the treatment of aggression and similar behavioralsyndromes.

The D5 receptor has very specific localization in the brain, and isfound in such areas as the Parafascicular Nucleus of the Thalamus, aswell as the prefrontal cortex, hippocampus, ventral tegmental area,Substantia Nigra and Raphe nucleus (Hartman D S, Civelli O. Molecularattributes of dopamine receptors: new potential for antipsychotic drugdevelopment. Ann Med 1996; 28(3):211-9). The Parafascicular nucleus isinvolved in the behavioral process of attention to critical sensoryinput and activation of the subject toward that stimulus. One of theimportant paradigms in which the Parafascicular nucleus participates isthe activation of the fight or flight response. Therefore, theParafascicular nucleus is likely involved in activating early componentsof aggressive behavior (Matsumoto N, Minamimoto T, Graybiel A M, KimuraM. Neurons in the thalamic CM-Pf complex supply striatal neurons withinformation about behaviorally significant sensory events. JNeurophysiol 2001; 85(2):960-76).

The gene for the D5, DRD5, is associated with impulsiveness and withsymptomology associated with disruptive behavioral disorders, such asantisocial personality disorder (Vanyukov M M, Moss H B, Kaplan B B,Kirillova G P, Tarter R E. Antisociality, substance dependence, and theDRD5 gene: a preliminary study. Am J Med Genet 2000; 96(5):654-8). DRD5is also associated with genetic transmission of a number of disordersassociated with aggression, irritability and impulsivity, includingschizophrenia, Tourette's and ADHD (Maher B S, Marazita M L, Ferrell RE, Vanyukov M M. Dopamine system genes and attention deficithyperactivity disorder: a meta-analysis. Psychiatr Genet 2002;12(4):207-15). Blockade of the D5 receptor in a knockout model isassociated with decreased motor activity, which may be akin to decreasedaggression (Holmes A, Hollon T R, Gleason T C, et al. Behavioralcharacterization of dopamine D5 receptor null mutant mice. BehavNeurosci 2001; 115(5):1129-44).

Molindone is a typical antipsychotic drug that has high affinity for D2family of dopamine receptors. where it is thought to exert itstherapeutic action. Molindone was previously suggested for the treatmentof aggression in both adult and pediatric patients (Greenhill L L,Barmack J E, Spalten D, Anderson M, Halpern F. Molindone Hydrochloridein the treatment of aggressive, hospitalized children [proceedings].Psychopharmacol Bull 1981; 17(1):125-7; Itil T M, Wadud A. Treatment ofhuman aggression with major tranquilizers, antidepressants, and newerpsychotropic drugs. J Nerv Ment Dis 1975; 160(2-1):83-99). Molindone wasalso evaluated for children with the early-onset schizophrenia spectrumdisorders (J Am Acad Child Adolesc Psychiatry, 2007, August, 46:8, p.969-978 and Am J Psychiatry, 165:11, November 2008).

For adults with schizophrenia, the dose of molindone may range from 100to 225 mg per day (Bagnall A, Fenton M, Kleijnen J, Lewis R. Molindonefor schizophrenia and severe mental illness. Cochrane Database Syst Rev2007 (1):CD002083). In general, the dose of other antipsychotics usedfor the treatment of aggressive behavior are about 50% relative to thoseused for the treatment of psychosis in schizophrenia (J Am Acad ChildAdolesc Psychiatry. 2006 July; 45(7):792-800).

SUMMARY OF THE INVENTION

The current invention offers a method of treatment of aggression and/orsimilar behavioral syndromes, including irritability and impulsivitythat comprises the steps of: 1. selecting several active agents withknown activity (e.g., agonist or antagonist) on at least onedopaminergic, serotonergic or gabaergic receptor where the oppositeactivity is associated with aggressive behavior; 2. conducting areceptor screening assay on these same receptor families with each ofthe active agents to identify activity for at least one additionalreceptor having a known association with undesired (i.e., aggressive)behavior; 3. determining if said activity is agonistic or antagonisticin nature; 4. by the results of steps 2 and 3, choosing among thescreened active agents at least one that targets the most diverse typesof aggression-associated receptors; 5. optimizing the total dose of theactive agent(s), taking into account results of steps 2 through 4; and6. administering the dose of step (5) to a mammalian subject.

In one embodiment of the invention, the mammalian subject is a humanchild. In another embodiment of the invention, the mammalian subject isan adult human.

Identification of agonist/antagonist activity in the active agents thatexhibit the potential as therapeutics for aggression and similarbehavioral syndromes is important, since it allows for selection ofdrugs that have more than one therapeutic target (e.g., both D2 and D5receptors). This is superior to taking a combination of therapies toachieve multiple targets because of the enhanced patient compliance withthe reduced pill load. It also can lead to a lower dose, since differentreceptor activities may be additive, or even synergistic, in theireffect.

Use of molecules that target a specific class of receptors with alimited distribution in the brain is also potentially beneficial in thatit limits the potential for side effects. This restricted set of neuralpathways is less likely to have “off-target” effect in the systems notinvolved in the desired activity.

In one embodiment, the invention comprises a method of treatment ofaggression and similar behavioral syndromes, such as impulsivity andirritability in a mammalian subject, by a pharmaceutical agentexhibiting combined D2 and D5 antagonistic activity.

In another embodiment, the invention discloses a method of treatment ofaggression and similar behavioral syndromes by a pharmaceutical agentexhibiting combined D2 and D5 antagonistic activity, wherein the totaldosage of the pharmaceutical agent is smaller than the dosageanticipated on the premise of D2 activity only.

In yet another embodiment of the invention, the pharmaceutical agent ismolindone.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a competition curve obtained with compound SPN-810M(molindone) at the human D5 receptor.

FIG. 2 shows the agonist effect of compound SPN-810M at the Human D5Receptor.

FIG. 3 shows the antagonist effect of compound SPN-810M at the Human D5receptor.

FIG. 4 shows a reduction in Conduct Problem Subscale Score achievedthrough administration of molindone in a randomized, multicenter,parallel group dose-ranging study in children with ADHD and persistentserious conduct problems.

FIG. 5 shows an adverse effect profile of molindone in a randomized,multicenter, parallel group dose-ranging study in children with ADHD andpersistent serious conduct problems

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It was unexpectedly discovered that, in addition to the well-documentedD2-receptor group antagonistic activity, molindone has specificantagonist activity at the D5 dopaminergic receptor.

A heterologous competition assay was designed for a receptor affinityscreening of molindone. Recombinant D5 receptors were expressed in a GH4cell line and specific binding was characterized by displacement ofanother molecule with affinity for the D5 receptor (the “ligand”).“Specific binding” refers here to the difference in the binding of theligand to the receptors in the presence and absence of an excess of theactive agent. An initial screen was performed with 10⁻⁵ μM molindone.The conditions and results of the assay are summarized in the Tables 1and 2.

TABLE 1 Conditions of the displacement assay for molindone Method ofAssay Ligand Conc. Non-specific Incubation detection D₁(h) [³H]SCH 0.3SCH 23390* 60 min./ Scintillation 23390 nM (1 μM) 22 °C. countingD_(2S)(h) [³H]spiperone 0.3 (+)butaclamol 60 min./ Scintillation nM (10μM) 22 °C. counting D₃(h) [³H]spiperone 0.3 (+)butaclamol 60 min./Scintillation nM (10 μM) 22 °C. counting D₅(h) [³H]SCH 0.3 SCH 23390 60min./ Scintillation 23390 nM (10 μM) 22 °C. counting *SCH 23390 is ahighly potent and selective dopamine D1-like receptor antagonist with aK(i) of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes,respectively.

TABLE 2 Results of the displacement assay for molindone (concentration1.0E−05M) Assay % Inhibition of control specific binding D1 55 D2s 98 D3100 D4.4 38 D5 59

The affinity of molindone for the D5 receptor was further characterizedby determining the IC50, or concentration that inhibits 50% of controlspecific binding. For this experiment, a range of molindoneconcentrations was selected for the ligand blocking assay. The IC50 wasdetermined using non-linear regression analysis of the competitioncurves using Hill equation curve fitting. The inhibition constants Ki,wherein Ki is defined as the concentration of the competing ligand(molindone) that will bind to half the binding sites at equilibrium inthe absence of radioligand or other competitors, were calculated usingCheng Prusoff equation. The results of the affinity assay are summarizedin Tables 3 and 4, and in FIG. 1.

TABLE 3 IC₅₀ Determination: Individual Data Test % of Control SpecificBinding Receptor Concentration(M) 1st 2nd Mean D₁(h) 3.0E−08 105.5 95.5102.0 1.0E−07 95.6 96.5 96.0 3.0E−07 93.4 92.6 93.0 1.0E−06 90.9 70.380.6 3.0E−06 52.2 56.8 54.5 1.0E−05 31.6 30.7 31.1 3.0E−05 18.4 12.615.5 1.0E−04 2.8 3.7 3.2 D_(2S)(h) 3.0E−10 99.1 95.6 97.3 3.0E−09 95.8104.6 100.2 1.0E−08 91.0 94.7 92.8 3.0E−08 68.0 71.9 69.9 1.0E−07 22.028.1 25.1 3.0E−07 4.4 1.9 3.1 1.0E−06 0.1 −0.7 −0.3 1.0E−05 −1.7 −3.0−2.4 D₃(h) 3.0E−10 98.4 100.0 99.2 3.0E−09 103.7 102.6 103.2 1.0E−08101.9 107.3 104.6 3.0E−08 99.3 90.6 94.9 1.0E−07 71.4 63.4 67.4 3.0E−0731.4 32.3 31.9 1.0E−06 8.1 9.1 8.6 1.0E−05 −1.0 0.9 −0.1 D₅(h) 3.0E−08123.6 115.3 1.0E−07 106.9 130.3 120.8 3.0E−07 111.2 132.3 120.9 1.0E−06109.6 118.9 104.7 3.0E−06 90.5 78.1 80.2 1.0E−05 82.2 43.4 34.9 3.0E−0526.3 18.3 18.5 1.0E−04 18.6 8.3 6.8

TABLE 4 IC50 Determination for Molindone: Summary Results ReferenceAssay compound IC₅₀ (M) K₁ (M) n_((H)) D1 SCH 23390 3.9E−06 1.5E−06 0.9D2s (+) butaclamol 5.1E−08 1.7E−08 1.7 D3 (+) butaclamol 1.6E−07 3.6E−081.4 D5 SCH 23390 5.2E−06 2.4E−06 1.2

The final step of the assay was to characterize whether the binding isof an agonist or antagonist nature. For the D5 receptor, this wasaccomplished through an assay that examined the agonist effect on the D5receptor, i.e., the generation of cAMP or the blockade of this effectwhen stimulated by a D5 agonist, dopamine. This was also done with arange of concentrations to determine the relative agonist vs antagonistbinding Ki. The EC₅₀ values (concentration producing a half-maximalspecific response) and IC₅₀ values (a concentration causing ahalf-maximal inhibition of the control-specific agonist response) weredetermined by non-linear regression analysis of theconcentration-response curves generated with mean replicate values usingHill equation curve fitting. The apparent dissociation constants forantagonists K_(b) were calculated using the modified Cheng Prusoffequation.

The conditions of the screening are presented in Table 5. It was foundthat molindone (10⁻⁵ μM) exhibited 59% inhibition of the SCH23390binding at the D5 receptor. The Ki was determined to be 2.4×10⁻⁶. Thebinding was determined to be that of an antagonist. The full results ofthe screening are summarized in Tables 6-8 and in FIG. 2-3.

TABLE 5 Agonist/Antagonist screening Assay: Conditions Incu- ReactionMethod of Assay Stimulus bation Product Detection D₁(h) None (10 μM 30min./ cAMP HTRF (agonist effect) dopamine for 22° C. (Homogeneouscontrol) Time Resolved Fluorescence) D₁(h) Dopamine 30 min./ cAMP HTRF(antagonist (1000 nM) 22° C. effect) D_(2S)(h) None (100 nM 20 min./cAMP HTRF (agonist dopamine for 37° C. effect) control) D_(2s)(h)Dopamine (30 20 min./ cAMP HTRF (antagonist nM dopamine 37° C. effect)for control) D₃(h) None (30 nM 10 min./ cAMP HTRF (agonist effect)dopamine for 37° C. control) D₃(h) dopamine (10 10 min./ cAMP HTRF(antagonist nM) 37° C. effect) D₅(h) None (10 μM 30 min./ cAMP HTRF(agonist effect) dopamine for 22° C. control) D5(h) Dopamine (100 30min./ cAMP HTRF (antagonist nM) 22° C. effect)

TABLE 6 IC₅₀ Determination for D₅ (h): Individual Data (AntagonistEffect) Agonist Response Test Concen - % of % of % of Control, tration(M) Control, 1^(st) Control, 2^(nd) Mean 1.0E−07 107 115 111.0 3.0E−0790 95 92.9 1.0E−06 98 95 96.4 3.0E−06 67 66 66.7 1.0E−05 40 36 38.42.0E−05 19 20 19.6 5.0E−05 4 11 7.3 1.0E−04 7 4 5.6

TABLE 7 IC₅₀ Determination: Summary Results (Antagonist Effect) ReceptorIC₅₀ (M) K_(B) (M) D₁(h) 3.1E−05 2.0E−06 D_(2S)(h) 6.8E−08 4.7E−09 D₃(h)1.1E−06 7.1E−08 D₅(h) 5.3E−06 9.2E−07

TABLE 8 EC₅₀ Determination for D₅ (h): Individual Data (Agonist Effect)Test Agonist Response Concentration % of % of % of (M) Control, 1^(st)Control, 2^(nd) Control, Mean 1.0E−07 2 2 2.1 3.0E−07 4 −1 1.8 1.0E−06 00 0.1 3.0E−06 3 4 3.3 1.0E−05 −1 2 0.6 2.0E−05 −2 2 0.2 5.0E−05 1 −2−0.7 1.0E−04 1 4 2.1

Based on the receptor findings, it was suggested that molindone may beeffective for the treatment of aggression in humans, in particular, inchildren with ADHD, in smaller doses than is currently customary. Alower daily dose of the drug results in a diminishing frequency andseverity of the adverse effects of the treatment to a level oftolerability, thus resulting in improvement in patient compliance.

In one embodiment, the invention is directed to a method of treatment ofaggression in humans, in particular children, diagnosed with ADHD,bipolar disorder, autism, and post traumatic stress disorder byadministering molindone in a total daily dose that is at least 10% lowerthan the current dose for its use as an antipsychotic agent. In otherembodiments, the dose is 15% lower, 25% lower, 35% lower, and 50% lowerthan the current dose.

In one embodiment of the invention, molindone is administered in a doserange of from 10 mg/day to 200 mg/day. In other embodiments, molindoneis administered in dose ranges of from 3 mg/day to 200 mg/day; 15 mg/dayto 120 mg/day; 15 mg/day to 90 mg/day; 30 mg/day to 90 mg/day; or 36mg/day to 72 mg/day.

The success of the treatment is evident in the marked decrease in thenumber instances of undesirable behavior exhibiting aggression,irritability and impulsivity. Such behavior may be exemplified, withoutlimitation, by disobedience; negativism; provocative opposition toauthority figures; violations of minor rules; temper tantrums;argumentativeness; provocative behavior; stubbornness; blaming othersfor his or her own mistakes; being touchy, easily annoyed, angry,resentful, spiteful or vindictive; and swearing.

In another embodiment, the invention encompasses a method of treatmentof aggression in children with ADHD with molindone that is characterizedby an improved adverse effect profile. The adverse effects that arediminished by the method of the present invention may be, but are notlimited to, drowsiness, depression, hyperactivity and euphoria,extrapyramidal reactions, akathisia, akinesia, dystonic syndrome,tardive dyskinesia, tachycardia, nausea, dry mouth, urinary retention,and constipation.

The efficacy and the adverse effect profile of the lower dose treatmentof the current invention were evaluated in a Randomized, Multicenter,Parallel Group, Dose Ranging Study to Evaluate the Safety andTolerability of molindone in Children withAttention-Deficit-Hyperactivity Disorder (ADHD) and Persistent SeriousConduct Problems, where the subjects are administered molindonehydrochloride given 3 times daily in a dose range of 5 to 20 mg/day inchildren <30 kg, and 10 to 40 mg/day in children ≥30 kg (Example 1 andFIG. 4).

Example 1

Effectiveness, safety and tolerability of molindone was evaluated in arandomized, multicenter, parallel group dose-ranging study in childrenwith ADHD and persistent serious conduct problems. Subjects wererandomized based on weight at baseline to 1 of 4 treatment groups. Thedosing for subjects with weight of less than 30 kg was initiated at 1.67mg/day and 3.34 mg/day for subjects weighing 30 kg or more. A titrationschedule was followed until the target dose (Treatment group 1, 2, 3 or4) was reached. Subjects remained at target dose for 6 weeks (Table 9).

TABLE 9 Total daily dose by treatment group Treatment TreatmentTreatment Treatment group 1 group 2 group 3 group 4 <30 kg  5 mg/day 10mg/day 15 mg/day 20 mg/day ≥30 kg 10 mg/day 20 mg/day 30 mg/day 40mg/day

The study showed a statistically significant efficacy signal towardsreducing Conduct Problem Subscale scores. (Table 10; FIG. 4).

TABLE 10 Mean Reduction from Baseline in NCBRF-TIQ: Conduct ProblemSubscale Score Treatment 1 Treatment 2 Treatment 3 Treatment 4 BaselineMean 20.35 25.74 26.00 25.95 Visit 12 Mean 13.40 17.00 17.79 11.65 MeanReduction 6.95 8.74 8.21 14.30

Side effects from the administration of molindone in all four treatmentgroups were mild, self-limiting and within the limits of tolerability,i.e. no subjects discontinued the study because of the side effects(FIG. 5).

What is claimed is:
 1. A method of treating impulsive aggression in apost-traumatic stress disorder (PTSD) patient, comprising: administering10 mg/day to 200 mg/day of molindone to a patient with PTSD as the solecondition and manifesting impulsive aggression not controlled by PTSDtreatment.
 2. The method of claim 1, wherein 15 to 120 mg/day ofmolindone is administered.
 3. The method of claim 1, wherein theadministration decreases side effects associated with molindone.
 4. Themethod of claim 3, wherein the side effects are selected fromdrowsiness, depression, hyperactivity, euphoria, extrapyramidalreactions, akathisia, akinesia, dystonic syndrome, tardive dyskinesia,tachycardia, nausea, dry mouth, urinary retention, and constipation. 5.The method of claim 1, wherein the administration results in reductionof undesirable behavior and intolerable side effects.
 6. The method ofclaim 1, wherein the patient is a child or an adult.